Glaucoma is the second leading cause of blindness in the United States, first among African Americans. In many cases, malformation of the eye, especially the iris and associated tissues, is the underlying cause of glaucoma. At present, little is known about basic mechanisms which contribute to normal iris development and therefore the pathology arising during abnormal development is not understood. The PI's laboratory has identified a new transcription factor, 1mx-1a, which is essential for normal iris development in mice. Mice which lack 1mx-1a have small eyes and a malformed iris. In the proposed research, the PI plans to extend our current findings in five distinct areas: First, the precise nature and timing of ocular developmental defects in our 1mx-1a mutant mice will be determined. Second, the functional relationship between 1mx-1a and other regulatory genes known to aniridia (total or partial loss of iris) and glaucoma in humans will be examined. Third, novel inductive mechanisms underlying anterior segment morphogenesis will be characterized using reagents we have generated and/or isolated. Fourth, the ability of cells lacking 1mx-1a to participate in normal eye development will be determined by the generation of chimeric mice. Finally, the human 1mx-1a gene will be isolated and mapped to determine if it may contribute to any hereditary glaucomas. Taken together, the proposed studies should lead to some of the first insights into important and essential molecular genetic mechanisms of anterior segment development. Progress in these areas will ultimately lead to fundamental advances in early diagnosis, treatment, and where possible prevention of pediatric and other hereditary glaucomas.